tbuckley/cabot-search huggingface dataset:
Abstract 145: Giant cells: A new paradigm to understand tumor origins and decode their complexity at the organismal level
Authors: Jinsong Liu
Journal: Cancer Research (2023)

Abstract Traditionally, human cancers have been considered genetic-based diseases characterized by somatic mutations. However, despite its wide acceptance, this simple concept cannot explain cancers’ numerous oncogenic driver mutations, structural genomic changes in normal and embryonic tissues, nuclear atypia, and lack of tissue differentiation. Due to these pitfalls, the cancer research community is searching for a new paradigm to explain the complexity of tumors and guide future research. Here I proposed a new hypothesis based on the observation of different tumors and their correlation with stages of early embryonic development in humans to explain human tumors' complexity and origin. I consider cancer a developmental disease of sexual or asexual origin. In tumors of sexual origin, the giant egg cell undergoes cleavage after fertilization to form blastomeres that generate genomic chaos via the rapidly increasing genomic contents of the zygote. The compacted embryo then forms a blastocyst, resulting in embryonic transformation and the formation of the trophectoderm. After implantation, the trophectoderm develops into a placenta, and the inner cell mass develops into a baby or a differentiated tumor resembling a specific embryonic tissue stage or fetal organ if one or more germ layers fail to complete differentiation. In tumors of asexual origin, the tumor starts with senescent somatic cells. Following environmental and genetic stresses, the senescent cells undergo escape via genomic duplication or multiplication, giving rise to polyploid giant cancer cells (PGCCs), the somatic equivalent of blastomeres. This leads to genome duplication or multiplication to create genomic chaos and the development of high-grade cancer with a high level of nuclear atypia, a process analogous to sexual-mediated pre-embryogenesis but without subsequent differentiation. This new hypothesis not only explains the different tumor entities and their benign and malignant natures but also provides a unified explanation of the chaotic genomics and somatic mutations of cancer during embryonic development. The evidence to support this hypothesis will be presented from the pathology, developmental, and genetic perspectives. The switch from conceiving cancer as a disease of mitosis-based cell proliferation to conceiving it as a disease arising from giant cell-mediated development provides a new paradigm to decode tumors' complexity, understand their origins at the organismal level, and guide future cancer research. Citation Format: Jinsong Liu. Giant cells: A new paradigm to understand tumor origins and decode their complexity at the organismal level [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 145.
Abstract 4779: MnSOD mimetic mitoquinone mesylate (MitoQ) increases DCLK1+pancreatic cancer stem cells
Authors: Jeffrey Mario Perera, Alicia K. Fleming Martinez, Peter Storz
Journal: Cancer Research (2023)

Abstract Mitochondrially-generated reactive oxygen species (mROS) have been shown to induce acinar-to-ductal metaplasia (ADM). ADM, in presence of an oncogenic KRAS mutation, is an initiating step for progression to pancreatic intraepithelial neoplasia (PanIN) and eventually pancreatic ductal adenocarcinoma (PDA). Here, we utilize primary murine cells as well as the p48Cre;LSL-KrasG12D (KC) mouse model to explore the use of the mitochondria-targeted mimetic of manganese superoxide dismutase MitoQ for targeting PDA initiation and progression. Previously published data by our laboratory has shown that treatment with MitoQ decreases the abundance of pancreatic low-grade lesions in KC mice. However, we here demonstrate that superoxide depletion by MitoQ at the same time increases formation of DCLK1+ cancer stem cells in such lesions. We here evaluate if the detoxification of mitochondrial superoxide results in a build-up of hydrogen peroxide, which is a major driver of the DCLK1+ cell type. We determine how altered expression of ROS detoxifying enzymes in different cell types contribute to PDA stem cell formation and PDA development. Eventually we test if the increase in DCLK1+ cancer stem cells can contribute to changes in the microenvironment and accelerated progression of abnormal tissue. Citation Format: Jeffrey Mario Perera, Alicia K. Fleming Martinez, Peter Storz. MnSOD mimetic mitoquinone mesylate (MitoQ) increases DCLK1+pancreatic cancer stem cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4779.
Abstract 2192: Potential of galectin-7 as differentiating biomarker of lung cancer subtypes
Authors: Avery T. Funkhouser, Jonah C. Shealy, Alexandra E. Kesic, Bailey B. Blair, Julie C. Martin, Connie M. Arthur, Christopher R. Funk, W. Jeffery Edenfield, Anna V. Blenda
Journal: Cancer Research (2023)

Abstract Background. Lung cancer is the leading cause of cancer-related death in both men and women in the United States. Non-small Cell Lung Cancer is the most prevalent and includes adenocarcinoma (AD), and squamous cell lung cancers. The unique cellular biology of these cancers could potentially allow for serological detection and identification via tissue specific protein markers. Galectins are a group of β-galactoside binding proteins which are known to be alternatively expressed in cancers and are being studied for their biomarker potential. Galectin-7 is expressed in epithelial tissues as well as in all layers of the epidermis as it is normally highly expressed by squamous cells. Purpose. We are evaluating potential of galectin-7 to be used as a serum biomarker and delineator of several lung cancer subtypes. Methods. The serum concentrations of galectin-7 were measured in 96 cancer patients using ELISA. Twenty-eight samples were from adenocarcinoma lung cancer patients, 25 were from squamous cell lung carcinomas patients, 19 were from all other types of lung cancer, and 28 were from other squamous cell carcinomas of non-pulmonary origin. The serum galectin-7 concentrations in cancer patients were compared amongst themselves by their histological subtypes. One-way analysis was performed using Student’s t-test for pairwise comparisons. Results. Galectin-7 concentrations were significantly elevated in serum samples from squamous cell lung cancer patients (n=25; mean, 1.91 ng/mL) relative to adenocarcinoma lung cancer patients (n=24; mean, 1.02; p-value, 0.0149). Additionally, levels of galectin-7 in samples of squamous cell lung carcinomas were higher than samples of squamous cell carcinomas of non-pulmonary origin (n=28; mean, 0.33 ng/mL, p-value, &amp;lt;0.0001). These results show that serum galectin-7 is increased in patients with squamous cell lung cancer compared to adenocarcinoma lung cancer. Conclusion. Potential clinical applications of this study include the measurement of galectin-7 in blood samples of cancer patients to aid in cancer screening and tumor type identification. Further explorations comprise measuring serum concentrations of galectin-7 by stage of squamous cell lung cancer and histological subtype (keratinizing, non-keratinizing, and basaloid) to determine a more nuanced understanding of the tumor molecular biology. Citation Format: Avery T. Funkhouser, Jonah C. Shealy, Alexandra E. Kesic, Bailey B. Blair, Julie C. Martin, Connie M. Arthur, Christopher R. Funk, W. Jeffery Edenfield, Anna V. Blenda. Potential of galectin-7 as differentiating biomarker of lung cancer subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2192.
Abstract 2352: ALDOC interplays with KIAA1409 to reduce m6A modifications and cancer-associated fibroblast characteristics in gliomas
Authors: Chien-Hsiu Li, Ming-Hsien Chan, Yu-Chan Chang
Journal: Cancer Research (2023)

Abstract The abundance and regulatory mechanisms of tumor microenvironment in gliomas remain unclear. We have previously demonstrated that aldolase c (ALDOC) has tumor suppressor function and prognostic value in the progression of glioma. In this study, we used immune infiltration algorithms to identify the immune response events that ALDOC modulates in gliomas and found that they were particularly strongly associated with cancer-associated fibroblasts (CAFs). Our transcriptomic and proteomic profiles infer that ALDOC is involved in the methylation status of N6-methyladenosine (m6A) and binds to KIAA1429, which in turn affects the assembly of the assembly of the m6A-METTL complex. We show that ALDOC can interact with KIAA1429 and trap it in the cytoplasm and then interfere with the modification of m6A. In malignant cells and ALDOC knockdown models, we observed loss of ALDOC function, KIAA1429 was responsible for the ‘writer’ of m6A and stabilized expression levels of various CAF-related features. Through the MeRIP-Seq/m6A-seq approach, we found that the RNA-binding protein, IGF2BP2, can be directly stabilized with multiple CAF-related genes. We examined ALDOC and KIAA1429, CAF-related genes (FAP, α-SMA, S100A4 and VIM) in available cohorts and tissue microarrays and were statistically inversely correlated. Furthermore, ALDOC colocalized with KIAA1429 and CAF genes in the surrounding microenvironment was significantly reduced in tissue sections from orthotopic animal models by multiplex immunohistochemistry. Keywords: Aldolase C, m6A modification, cancer-associated fibroblasts, gliomas Citation Format: Chien-Hsiu Li, Ming-Hsien Chan, Yu-Chan Chang. ALDOC interplays with KIAA1409 to reduce m6A modifications and cancer-associated fibroblast characteristics in gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2352.
Abstract 3131: Anaplastic transformation model in thyroid cancer revealed by single cell lineage and fate analysis
Authors: Lina Lu, Jennifer Rui Wang, Ying C. Henderson, Shanshan Bai, Jie Yang, Min Hu, Yuanqing Yan, Tuan M Tran, Jianzhuo Li, Cheng-Kai Shiau, Rachel Kieser, Xiao Zhao, Jiping Wang, Roza Nurieva, Michelle D. Williams, Maria E. Cabanillas, Ramona Dadu, Naifa Lamki Busaidy, Mark Zafereo, Nicholas Navin, Stephen Y. Lai, Ruli Gao
Journal: Cancer Research (2023)

Abstract The deadliest anaplastic thyroid cancer (ATC) often transforms from indolent differentiated thyroid cancer (DTC), however the complex intra-tumor transformation process is poorly understood. We investigated an anaplastic transformation model by dissecting both cell lineage and cell fate transitions using single cell transcriptomes and genetic alterations data of patients with different subtypes of thyroid cancer. The resulting model started from stress-responsive DTC cells to inflammatory ATC cells, to mitotic defective ATC cells and extended all the way to mesenchymal ATC cells. In parallel with tumor cell evolution, macrophages shifted from anti-tumor to tumor-promoting states and T cells reprogrammed from cytotoxic to exhausted states. Further, our analysis identified two important milestones: 1) diploid stage, where ATC cells were commonly diploids with non-RAS mutations and inflammatory phenotypes. 2) aneuploid stage, where ATC cells gained aneuploidy with frequent RAS mutations and mesenchymal phenotypes leading to the extreme lethal stage of ATC progression. Citation Format: Lina Lu, Jennifer Rui Wang, Ying C. Henderson, Shanshan Bai, Jie Yang, Min Hu, Yuanqing Yan, Tuan M Tran, Jianzhuo Li, Cheng-Kai Shiau, Rachel Kieser, Xiao Zhao, Jiping Wang, Roza Nurieva, Michelle D. Williams, Maria E. Cabanillas, Ramona Dadu, Naifa Lamki Busaidy, Mark Zafereo, Nicholas Navin, Stephen Y. Lai, Ruli Gao. Anaplastic transformation model in thyroid cancer revealed by single cell lineage and fate analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3131.
Abstract 3970: NCG-hIL15 humanized mice: an ideal model for human immune reconstitution of NK cells
Authors: Xing Liu, Meirong Wu, Huiyi Wang, Weiwei Yu, Jianming Xu, Hongyan Sun, Cunxiang Ju, Hongyu Wang, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao
Journal: Cancer Research (2023)

Abstract Introduction: IL-15 is a four α-helix bundle cytokine which is produced by dendritic cells, monocytes, and epithelial cells. IL-15 is necessary for the development, survival, and activation of natural killer (NK) cells. NK cells are unable to persist in immunodeficient NCG mice reconsituted with human NK cells, but after knocking in human IL-15 (hIL-15), NCG-hIL15 mice can support the reconstitution and survival of human NK cells. Results: Compared with NCG mice, the level of hIL-15 was significantly increased in NCG-hIL15 mice. After transplanting human PBMC (huPBMC) or NK (huNK) cells into NCG-hIL15 mice, the peripheral blood level of NK cells in huNK-NCG-hIL15 mice was much higher than in huPBMC-NCG-hIL15 mice. The expression of perforin in peripheral blood of huNK-NCG-hIL15 mice was significantly higher than that in huPBMC-NCG-hIL15 mice. Considering the obvious ADCC of rituximab acting on Raji cells in vitro, we evaluated the efficacy of rituximab in huNK-NCG-hIL15 mice subcutaneously engrafted with Raji cells. Rituximab significantly inhibited the tumor growth in huNK-NCG-hIL15 mice. Conclusion: NCG-hIL15 is a great mouse model to evaluate the anti-tumor efficacy of drugs targeting human NK cells without the interference of T cells. Citation Format: Xing Liu, Meirong Wu, Huiyi Wang, Weiwei Yu, Jianming Xu, Hongyan Sun, Cunxiang Ju, Hongyu Wang, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao. NCG-hIL15 humanized mice: an ideal model for human immune reconstitution of NK cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3970.
Abstract 3094: Discovery of a HeliconTM peptide inhibitor of the beta-catenin-TCF interaction with <i>in vivo</i> activity
Authors: Brian H. White, Yaguang Si, Sarah Cappucci, Zhi Li, Jessica D. Ramirez, Charles M. Ponthier, Erica Visness, Peicheng Du, Minjung Choi, Pieter C. Beerepoot, Paula C. Ortet, Ivan T. Jewett, Josue Alfaro-Lopez, Sorabh Agarwal, Daniel La, Aaron Fulgham, John H. McGee, Keith Orford, Jonathan B. Hurov, Martin R. Tremblay, Gregory L. Verdine
Journal: Cancer Research (2023)

Abstract Wnt signaling pathway mutations leading to constitutive activation of the driver oncogene β-catenin occur in at least 20% of all human cancers, but β-catenin itself has remained undruggable by traditional modalities. In order to inhibit the activity of β-catenin, we have developed conformationally hyperstabilized α-helical peptides (Helicons) that are cellularly permeable and bind directly to β-catenin in order to block its interaction with TCF family of transcription factors. Starting with a helical peptide derived from phage display, a combination of structural biology insights and medicinal chemistry optimization improved β-catenin binding of lead peptides to picomolar affinity. Cellular permeability was achieved by modification of physical properties as well as cyclization strategies to enforce helicity and manage backbone amide bonds. Helicons show excellent pharmacokinetic profiles suitable for intermittent dosing. β-catenin targeting helicons demonstrate on-target activity and potent inhibition of Wnt-driven tumor growth in vivo. Citation Format: Brian H. White, Yaguang Si, Sarah Cappucci, Zhi Li, Jessica D. Ramirez, Charles M. Ponthier, Erica Visness, Peicheng Du, Minjung Choi, Pieter C. Beerepoot, Paula C. Ortet, Ivan T. Jewett, Josue Alfaro-Lopez, Sorabh Agarwal, Daniel La, Aaron Fulgham, John H. McGee, Keith Orford, Jonathan B. Hurov, Martin R. Tremblay, Gregory L. Verdine. Discovery of a HeliconTM peptide inhibitor of the beta-catenin-TCF interaction with in vivo activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3094.
Abstract 2977: A first-in-class anti-HER2/TROP2 bispecific antibody-drug conjugate (YH012) exhibits potent anti-tumor efficacy
Authors: Chengzhang Shang, Gao An, Yuming Guo, Ellen Zhang, Qingcong Lin, Yi Yang
Journal: Cancer Research (2023)

Abstract Antibody-drug conjugates (ADC) are a therapeutic modality that combines the advantages of potent killing from small molecule cytotoxic payload and highly specific targeting from monoclonal antibodies. By targeting dual tumor-associated antigens (TAA), the bispecific ADC (BsADC) serves as a promising therapeutic strategy that can further increase tissue specificity and selectivity. HER2 and TROP2 are two TAAs that are commonly expressed and co-expressed by multiple tumor types, including gastric, colorectal, bladder, breast, and non-small-cell lung cancer (NSCLC). Of note, TROP2 expression has been detected in a wide range of HER2-low expressing tumors. These data led us to predict that targeting HER2 and TROP2 with a BsADC would provide therapeutic benefit, especially for patients with HER2-low cancers. Hence, we generated YH012, a first-in-class BsADC that contains a fully human bispecific anti-HER2/TROP2 antibody conjugated with monomethyl auristatin E (MMAE) via a protease-cleavable linker. In vitro, YH012 demonstrated enhanced affinity, internalization, and tumor selectivity compared to its parental monoclonal and monovalent anti-HER2 or anti-TROP2 antibodies. In vivo, YH012 showed strong anti-tumor activity in multiple cell line-derived and patient-derived xenografts (CDX and PDX) of NSCLC, gastric, pancreatic, and breast cancer. Moreover, YH012 exhibited superior anti-tumor efficacy than benchmark antibodies in both HER2-positive and HER2-low xenograft models, indicating that YH012 has a potent and broad therapeutic effect. In summary, YH012 has the advantages of increased potency, tissue specificity, and reduced toxicity as a novel BsADC that can be further exploited to treat HER2 and TROP2 co-expressing tumors, especially HER2-low tumors. Citation Format: Chengzhang Shang, Gao An, Yuming Guo, Ellen Zhang, Qingcong Lin, Yi Yang. A first-in-class anti-HER2/TROP2 bispecific antibody-drug conjugate (YH012) exhibits potent anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2977.
Abstract 3255: Investigate immune regulation and therapeutic efficacy via regorafenib combined with PD-L1 inhibitor in glioblastoma
Authors: Dai-Cheng Dong, Yu-Chiang Liu
Journal: Cancer Research (2023)

Abstract Glioblastoma (GBM) is one of the most common aggressive primary brain tumors, with poor survival despite after surgery, radiation treatment, and chemotherapy. Regorafenib, a tyrosine kinase inhibitor used for cancer treatment, was known to effectively inhibit angiogenesis and attenuate the activity of oncogene receptor hormones. Currently, regorafenib has been approved to treat various cancer with significant improvement. Though regorafenib show potential to penetrate blood brain barrier, the role of regorafenib in glioblastoma has not been elucidated. With the finding of central nervous lymphatic system, immune checkpoint inhibitor (programmed cell death protein-1 and its ligand) therapy has ongoing with clinical trial in GBM. The PD-L1 on tumor cells may interact with the PD-1 on T cells, and therefore inhibited the proliferation of T cells proliferate and finally cause the immune escape of tumor. While the therapeutic efficacy of using immune checkpoint inhibitor alone is still not significant enough for GBM; thus, it is necessary to find other suitable drugs for combination. Moreover, patient with low PD-L1 expression may not be able to administrate with anti-PD-L1 therapy. Therefore, identifying suitable combination reagent to regulate PD-L1 expression and to enhance efficacy of anti-PD-L1 therapy is important. Our experiment aims to explore whether regorafenib can increase the transcription of PD-L1 via regulating β-catenin-related signal transduction, and thus enhancing the treatment efficacy of immune checkpoint inhibitor (anti-PD-L1) on GBM. Here, we used GL-261 animal model to prove the regulation of regorafenib combined with anti-PD-L1. According to our data, regorafenib can inhibit the proliferation and induce the apoptosis pattern in GBM cells. Further, regorafenib may induce PD-L1 expression via activating β-catenin-related signaling; and therefore, increasing the targeting efficacy of anti-PD-L1 in GBM. Not only induce PD-L1 expression, regorafenib combined with anti-PD-L1 may also induce the accumulation of active cytotoxicity T lymphocytes (CD8+IFN-γ+) and reduce the accumulation of immunosuppressive cells, such as regulatory T cells (CD11b+Gr-1+) and myeloid-derived suppressor cells (CD4+CD25+FOXP3+). In conclusion, our animal experiments suggested that regorafenib may effectively promote PD-L1 transcription in glioblastoma by up-regulating β-catenin-related signaling, thereby increasing the therapeutic target efficacy and effectiveness of immune checkpoint inhibitors. Citation Format: Dai-Cheng Dong, Yu-Chiang Liu. Investigate immune regulation and therapeutic efficacy via regorafenib combined with PD-L1 inhibitor in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3255.